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FENIB

MIM.604218

Tuesday 24 January 2006

Pathology

- germline mutations of PI12 in familial encephalopathy with neuroserpin inclusion bodies (FENIB) (MIM.604218)

Pathogenesis

- FENIB (familial encephalopathy with neuroserpin inclusion) bodiesis an inclusion body dementia. FENIB is an autosomal-dominant dementia that is characterized by eosinophilic neuronal inclusions of neuroserpin (Collins bodies) in the deeper layers of the cerebral cortex and the substantia nigra.

The inclusions are PAS positive and diastase resistant, and they bear a striking resemblance to those of Z alpha1-antitrypsin that form in the liver.

FENIB is associated with a mutation, S49P (S53P on the alpha1-antitrypsin template), in the neuroserpin gene that was homologous to one in alpha1-antitrypsin that causes cirrhosis (S53F) strongly indicated a common molecular mechanism.

This was confirmed by the finding that the neuronal inclusion bodies of FENIB were formed by entangled neuroserpin polymers that were identical in morphology to those from inclusion bodies present in hepatocytes from a child with alpha1-antitrypsin-deficiency-related cirrhosis.

Moreover, we have recently shown that recombinant S49P neuroserpin polymerizes much faster than the wild-type protein.

The direct relationship between the magnitude of the intracellular accumulation of neuroserpin and the severity of disease has been clearly shown by the recent identification of other neuroserpin mutations in families with FENIB.

In the original family, with the S49P neuroserpin mutation, the affected family members had diffuse, small, intraneuronal inclusions of neuroserpin, and an onset of dementia between the ages of 45 and 60 years. In a second family, with a conformationally more severe mutation (S52R) and larger inclusions, the onset of dementia was in early adulthood. In a third family, with yet another mutation (H338R), there were more inclusions than for the S52R mutation, and the onset of dementia took place in adolescence.

However, the most striking example was the family with the most ’polymerogenic’ mutation of neuroserpin, G392E. This replacement of a consistently conserved residue in the shutter region resulted in large, multiple inclusions in every neuron, with affected family members dying by the age of 20 years.

So, FENIB shows a clear genotype-phenotype correlation, with the severity of disease correlating closely with the propensity of the mutated neuroserpin to form polymers.

These findings, in addition to previous evidence of the correlation between the polymerization rate of alpha1-antitrypsin mutants and cirrhosis8, strongly indicate that intracellular protein aggregation is by itself sufficient to cause neurodegeneration.

The role of post-translational degradation of neuroserpin polymers in the development of neurotoxicity has yet to be determined.

See also

- conformational diseases

  • serpinopathies

- dementias
- neurdegenerative diseases

References

- Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: 12360234